? Project 2 Kidney stone disease affects about 1 in 11 Americans and imposes a significant economic burden on the healthcare system. The most common treatments are shock wave lithotripsy (SWL) and ureteroscopy (URS), which use noninvasive or minimally invasive techniques to break stones so that small fragments either pass naturally or can be removed. Although these approaches provide significant improvements over open surgery, they often involve retreatment, can cause injury to the kidney or ureter, and require significant resources such as a surgical suite and anesthetics. To address these limitations, burst wave lithotripsy (BWL) may provide an effective, safe, in-office treatment approach for a urologist to break stones. BWL is a new noninvasive approach that is currently in development toward clinical trials. BWL treatments can be delivered by a small system that is readily integrated with other ultrasound technologies for stone imaging and pushing. BWL uses short bursts of sub-megahertz ultrasound to break stones into uniform fragments and has been demonstrated to reliably break many types of natural stones with exposures that produce little, if any, injury in porcine kidneys. As BWL continues to advance toward clinical use, challenges related to variability among individual patients should be addressed to maximize the success of a given treatment and to expand the range of treatable conditions. For current implementations of BWL, variability in vivo has been observed in the onset of cavitation behaviors that may lead to both injury and shielding of the stone from effective treatment. Because treatment monitoring with ultrasound (US) imaging has been shown to enable real-time detection of the onset of injurious cavitation activity, the potential to adaptively select and modify BWL treatment parameters is apparent. The first Aim of this proposal comprises a series of in vitro and in vivo experiments to understand how stones affect cavitation and to correlate cavitation metrics derived from US imaging and backscatter with fragmentation. These data will be supplemented by simulations from Aim 3 with a validated numerical model of cavitation in the vicinity of the stone to develop strategies for adapting treatment parameters. Aims 2 and 3 of this proposal focus on understanding and exploiting mechanisms of stone fracture to develop advanced BWL treatment strategies. Aim 2 involves experimental testing of strategies for spatially and temporally manipulating BWL exposures to improve fragmentation. Aim 3 employs numerical simulation tools to identify fracture mechanics in different stone geometries and inform strategies for inducing and detecting fracture in other Aims. The proposed studies are designed synergistically with clinical trials in Projects 1 and 3, studies on stone imaging and manipulation in Project 1, and studies on BWL-related injury in Project 3. The work will benefit public health by improving the success of BWL as a noninvasive alternative for stone patients.